Abstract [en]

Human exposures to metals, metalloids, and their compounds frequently occur as mixtures, and hence it is important to consider the joint action of these elements in terms of both mechanisms of action and risk assessment purposes. The joint action of these elements may produce additive, synergistic/potentiating, or antagonistic effects that may be manifested as direct cellular toxicity (necrosis or apoptosis) or carcinogenicity. Dose-response relationships may be further influenced by constitutive factors such as age, sex, and the expression of specific proteins. Mechanisms of importance for the development of potentiated or antagonistic toxicity are the expression of metal-binding proteins (metallothioneins or lead-binding proteins) and interference with metal transporters such as DMT-1 and ZIP. Compared to men, women of childbearing age absorb more Cd from the gastrointestinal tract because they have lower iron stores than men. Another example of synergism that occurs in humans is the one between inorganic arsenic and cadmium in inducing kidney toxicity. In many cases, however, direct primary data on the joint action of toxic or essential elements are lacking, and so innovative derivative methods such as the binary weight-of-evidence method have been used to predict potential interactions among groups of metals and metalloids. At present, there is much to be learned about the joint action of both toxic and essential elements, and this is clearly a critical area of research.